Guarire di LLC senza trapianto è oggi possibile?

Moderatori: L. Guardigni, P.L. Zinzani

Impiegando la chemioterapia

convenzionale?

Francesca R Mauro

Dipartimento di Biotecnologie

Cellulari ed Ematologia

Università Sapienza, Roma

Guarire di LLC senza trapianto,

Impiegando la chemioterapia convenzionale

è oggi possibile?

Outline

Cure of CLL: criteria

Cure with HSCT: how many patients?

Cure with CIT: how mant patients?

Cure or mantain a disease control?

It is possible to eradicate CLL cells?

No clinical signs of CLLCR

No residual disease at flow-cytometry/PCR MRD negative

Persiting MRDneg-CR relapse-freesurvival (PFS >5 years?)

Cure of CLL

MRD negativity

Sensitivity of approximately one CLL cell in ≥10.000 leucocytes

detected by:

Immunophenotype (flow-MRD)

>4 color flow-cytometry

IGH rearrangement (ASO-PCR MRD)

Allele-Specific Oligonucleotide PCR (ASO-PCR)

MRD negativity= less than one CLL cell per 10-4 leucocytes

Is it meaningful to reach MRD negativity?

How many patients are cured after

allogeneic after HSCT?

Long-term follow-up for RIC allogeneic SCT in CLL

Mato and Porter, Blood 2016

Allogeneic HSCT for poor-risk CLL: dissecting immune-modulating

strategies for disease eradication and treatment of relapse

Hahn et al. BMT 2015

29% “cured” at 12 months

How many cured of CLL with allogeneic SCT

How many cured of CLL with SCT

Allogeneic HSCT for poor-risk CLL: dissecting immune-modulating

strategies for disease eradication and treatment of relapse

Relapse incidence by MRD status (a) and MRD recurrence (b) in patients who were event free at the 12-month landmark. (a) MRD-negative at the 12-month landmark immediately after HCT; light-green curve, MRD-negative at the 12-month landmark after immunomodulation; and red curve, MRD-positive at the 12-month landmark. (b) Dark-blue curve, MRD-negative at the 12-monthlandmark immediately after HSCT; and light-blue curve, MRD-negative at the 12-month landmark after immunomodulation.

Hahn et al. BMT 2015

How many patients are cured after

chemoimmunotherapy?

CLL8 study - FCR vs FC

Hallek M, et al. Lancet. 2010

817 patients

with untreated,

active CLL and

good physical

fitness

CIRS ≤ 6

CrCL ≥ 70 mL/min)

R

FCR

FC

Response Progression-Free Survival Overall Survival

CLL 8: OS and PFS: FCR vs FC

Fisher et al., Blood 2015

Median OS: FC 86.0 months FCRnot reached

Median PFS: FC 32.9 months FCR 56.9 months

OS PFS

CLL8 Trial: PFS in Genomic Subgroups

FC

FCR

17p- (n = 51)

11q- (n = 142)

+12q (n = 61)

13q- (n = 224)

Normal (n = 138)

PF

S

Stilgenbauer S, et al. Blood. 2014

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 0 12 24 36 48 60 72 84 96

Mos

Del 17p and TP53 mutations: effect on survival

PFS and MRD level at response

Bottcher et al., JCO 2012

Eradication of BM MRD may prompt early treatment discontinuation in CLL

237 patients with CLL treated with front-line FCR at MDACC MRD assessed by 4-color flow cytometry in BM after course 3 and at final response

MRD negative cases: 17% after course 3; 43% at final response assessment Mutated IGVH and trisomy 12 independently associated with MRD-negative status

Patients with a MRD-negative status showed a significantly longer PFS and OS independently of the number of courses received, 3 or 6 Early MRD eradication may propt consideration of early discontinuation of treatment. Such a strategy could reduce secondary complications (infection, myelosuppression, MDS/AMLother malignancies Strati et al., Blood 2014

Outcome of CLL patients treated with FCR by Risk and MRD

Fink et al., Leukemia 2013

PFS OS

Patients with low or intermediate MRD levels and no adverse biologic factors show a significantly better PFS and OS

High risk (29% of patients)- Median PFS 22 months; median OS: 64 months high MRD levels intermediate MRD levels plus TP53 aberrations and/or unmutated IGHV status Low Risk (71% of patients)- Median PFS 68 months; median OS not reached low MRD levels (<10−4) irrespective of any additional feature intermediate MRD levels with no unmutated IGHV genes nor a TP53 aberration

P<0.0001 P<0.0001

Low Risk

Low Risk

High Risk

High Risk

The lessons from patients treated with FCR

The outcome of patients strongly

related to:

IGVH mutational status

FCR300 and CLL8 PFS by IGVH mutation status

300 CLL patients treated with frontline FCR at the MDACC

P<.0001

60% IGVH mutated Prog-free @ 9yr

817 CLL patients treated with frontline FCR or FC in the CLL8 trial

>50% IGVH mutated Prog-free @ 6yr

P<.0001

Elderly patients with CLL frequently have comorbidities

Median age of CLL patients at diagnosis: 72 years1

Median age at first treatment 75 years

The number of comorbidities increases with age

1 Ries LAG et al. SEER Cancer Statistics Review 1975–2005. 2 Yancik R. Cancer 1997; 80:1273–83.

Age at CLL

diagnosis

(years)

Patients1

(%)

Mean

comorbidities2

(all cancer

types, n)

≤54 11 n/a

55–64 19 2.9

65–74 27 3.6

75+ 43 4.2

Mean no. of co-morbidities

2.9

3.6

4.2

n/a

The German CLL10 Trial: FCR vs BR

Eichhorst et al., ASH 2014, Abstarct # 19

Best Response MRD-negativity (<10-4 ) in PB and BM at response

Primary Endpoint: PFS after 24 months

non inferiority of BR vs FCR [HR (ү BR/FCR)] <1.388

Can BR regimen improve the results of FCR in fit patients ?

CLL11 - MRD at the end of treatment

CHL+GA101 CHL+GA-101: MRD+ vs MRD-

Goede et al NEJM 2014

CHL+R vs

Chlorambucil plus ofatumumab versus chlorambucil alone in

previously untreated patients with CLL (COMPLEMENT 1)

All pts

CR pts

69%

Response

Characteristics of patients

MRD at the end of treatment

Hillmen et al., Lancet 2015

p<0.0001

O-CHL

221

O-CHL

226

O-CHL

mPFS 22.4 months

CHL

mPFS 13.1 months

O-CHL

CHL

447 patients, median age 69 years

Clinical significance of posttreatment MRD analysis as determined by a method with sensitivity of at least 10-4, after first-linecombination chemotherapy or chemoimmunotherapy

Thompson and Wierda, Blood 2016

Cure of CLL

Some evidence that a little proportion of patients (20-28%)

with a very favorable clinical and genetic profile is probably

cured with FCR:

≤65 years, fit

IGVH mutated

favorable FISH profile

In this era the treatment paradigm is shifting from one of

potential cure at high risk to one of long-term disease

control with new chemo-free regimens.

Is the “cure” of CLL a still a target of treatment?